The interaction between the stroma and primary tumors, or their metastases, is essential for fixation of oncogenic mutations. This cross-talk is mediated by a large group of growth factors, whose prototype is the neuregulin family of EGF-like molecules. Neuregulins and their membrane receptors of the ErbB group of transmembrane tyrosine kinases constitute a signaling network. His previous analyses characterized a heterodime comprising a kinase-defective neuregulin receptor (ErbB-3) and a ligand-less oncogenic co-receptor (ErbB-2) as the most potent receptor species of the network. He hypothesizes that a neuregulin-driven ErbB-2.ErbB-3 heterodimer is a major proliferative engine of epithelial tumors. The following lines of research will test this scenario and its implications to the development of therapeutic strategies: (i) Ligands and their antagonists: Apparently, the heterodimer is a promiscuous receptor for multiple stromal ligands, probably because they all share a bivalent structure. New ligands that will become available through the Human Genome Project will be synthesized and tested for binding to the heterodimer or to an Erbb-2 homodimer. The information accumulated will be used to design antagonists of the heterodimer. (ii) Signaling pathways and their inhibitors: The biochemical mechanisms underlying the extremely potent proliferative action of the heterodimer will be investigated by using a yeast two-hybrid screen and a chimeric receptor approach. Synergy between immunotherapy, chemotherapy and inhibitors of the identified pathway(s) will be examined in model systems of tumor growth. (iii) Intracellular routes and their modifiers: He hypothesizes that endocytic routing of the heterodimer to recycling, rather than to degradation, contributes to its signaling potency. This model will be examined by using mutant receptors, and the recycling machinery characterized in details. The suspected cancer-inhibitory activity of drugs interfering with ErbB routing will be tested in vivo.